Acta Biomaterialia最新文献

{"title":"Toward preclinical evaluation of a thermosensitive PEG-poly(L-alanine) hydrogel: A study on sterilization, storage stability, and in vivo performance","authors":"Xin Wang,&nbsp;Zhiyong Chen,&nbsp;Zixuan Wang,&nbsp;Liwei Zhang,&nbsp;Jiandong Ding,&nbsp;Lin Yu","doi":"10.1016/j.actbio.2025.08.042","DOIUrl":"10.1016/j.actbio.2025.08.042","url":null,"abstract":"<div><div>Poly(amino acid)-based thermosensitive hydrogels hold great potential for clinical translation. Herein, we employ a thermosensitive methoxy poly(ethylene glycol)-<em>block</em>-poly(_L-alanine) (mPEG-PAla) hydrogel that undergoes a sol-to-gel transition upon heating as the model system to systematically evaluates its sterilizability, storage stability, in vivo degradation and in vivo drug release profiles—critical factors for clinical translation. mPEG-PAla copolymers are synthesized via ring-opening polymerization using the optimized amount of crown ether as the catalyst, ensuring controlled polymerization while minimizing catalyst usage. The powder form of the synthesized polymer facilitates efficient UV irradiation sterilization, and its aqueous solution can be rapidly prepared within 15 min. When pre-loaded into syringes, the mPEG-PAla hydrogel demonstrates storage stability for over 6 months. After subcutaneous injection into mice, traditional anatomic observation combined with nondestructive fluorescence imaging and magnetic resonance imaging (MRI) confirms that the mPEG-PAla hydrogel exhibits a stable in vivo degradation pattern, persisting for over 1.5 months, and its degradation products are metabolized primarily by the liver and kidneys. Histological analysis and MRI further validate the good biocompatibility of hydrogel. Fluorescence imaging reveals that the in vivo release profiles of three distinct fluorescent molecules, used as model drugs, present significant differences but follow the first-order release kinetics.</div></div><div><h3>Statement of significance</h3><div>Intelligent hydrogels have garnered significant attention for various biomedical applications. Nevertheless, few have entered clinical practice, and their successful clinical translation depends on fundamental research related to effective sterilization, long-term storage stability, and in vivo fate estimation. In this study, we systematically evaluated the translation potential of an injectable and thermosensitive mPEG-PAla hydrogel by optimizing the synthesis of mPEG-PAla copolymer and validating its sterilization efficacy, convenience of preparation, storage stability, in vivo degradation and in vivo drug release profiles. This study enhances the understanding of PEG-poly(amino acid) hydrogels and provides valuable insights for their preclinical studies and future applications.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 346-361"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An anisotropic cardiac patch with barbed microneedles for enhanced tissue anchorage and myocardial repair","authors":"Mengqi Shan ,&nbsp;Leqian Wei ,&nbsp;Zeqi Yang ,&nbsp;Yimeng Li ,&nbsp;Ruolan Deng ,&nbsp;Xinzhe Zhao ,&nbsp;Fujun Wang ,&nbsp;Guixue Wang ,&nbsp;Lu Wang ,&nbsp;Jifu Mao","doi":"10.1016/j.actbio.2025.08.060","DOIUrl":"10.1016/j.actbio.2025.08.060","url":null,"abstract":"<div><div>Microneedle patches can penetrate the myocardium to facilitate integration with cardiac tissue, offering a promising approach for myocardial infarction (MI) repair. However, their clinical translation has been hindered by insufficient fixation stability during cardiac contractions and mismatch with myocardial anisotropy. To address these challenges, a bioinspired three-dimensional cardiac patch integrating barbed microneedles and an anisotropic lightweight mesh was designed. The microneedle with outward-expanding barbs (OEBMN) demonstrated 10.8-fold stronger tissue anchorage than the barbless microneedle, while achieving a 6-fold reduction in the force ratio (insertion force/pulling-out force), indicating an enhanced anchoring performance. The OEBMN enabled sutureless patch transplantation onto the epicardium, ensuring more uniform stress distribution than suture-fixation systems where stress concentrations typically occur at knotting sites. The knitted mesh exhibited sufficient strength to provide long-term mechanical compensation to the infarcted myocardium, whereas the honeycomb-like structure satisfied the native myocardial anisotropy. Furthermore, the cardiac patch promoted comprehensive mechanical integration with the infarcted heart through OEBMNs, enabling multi-directional support from the inner myocardium to the epicardium. The rat MI model experiments revealed that the patch not only improved cardiac function and electrophysiological characteristics but also increased ventricular wall thickness, reduced fibrosis, and promoted angiogenesis. Transcriptome sequencing revealed that the potential mechanisms by which the patch promotes myocardial repair mainly include inhibiting apoptosis- and fibrosis-related pathways. Overall, this study proposes a sutureless fixation strategy for cardiac patches and highlights the latent potential of providing anisotropic mechanical support for MI repair.</div></div><div><h3>Statement of significance</h3><div>Microneedle patches offer a promising platform for myocardial repair by directly penetrating cardiac tissue and enabling mechanical integration with the tissue. However, their application is hindered by limited fixation stability and structural mismatch with anisotropic myocardium. Herein, a cardiac patch combining an anisotropic lightweight mesh with microneedles featuring outward-expanding barbs was constructed. This design allows stable anchoring, sutureless implantation with reduced insertion force, uniform stress transmission, and anisotropic mechanical support to inhibit ventricular dilation. <em>In vivo</em> results showed that the patch significantly enhanced cardiac contractile function, reduced ventricular fibrosis, and increased ventricular wall thickness. This unique design demonstrates substantial potential for sutureless fixation scenarios and the repair of infarcted myocardium.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 505-520"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulfonium lipid nanoparticles for intranasal mRNA delivery to lung epithelial and immune cells","authors":"Yuqin Men ,&nbsp;David O. Popoola ,&nbsp;Zhi Cao ,&nbsp;Yiran Li ,&nbsp;Stephan Wilkens ,&nbsp;Yong Teng ,&nbsp;Qinghe Meng ,&nbsp;Marc Hershenson ,&nbsp;Yamin Li","doi":"10.1016/j.actbio.2025.08.032","DOIUrl":"10.1016/j.actbio.2025.08.032","url":null,"abstract":"<div><div>Lung epithelial and immune cells play an important role in respiratory health, serving as the first line of defense. Targeting these cells presents significant therapeutic opportunities, particularly for mRNA-based medicine. However, efficient mRNA delivery to lung cells remains challenging due to mucosal barriers, enzymatic degradation, and complex tissue architecture. In this study, we developed sulfonium lipid nanoparticles (sLNPs) featuring a sulfonium head group and branched tail structure. These sLNPs efficiently delivered mRNA to lung epithelial and immune cells via intranasal instillation in mice, transfecting club cells, ciliated cells, and macrophages, which are key players in lung structure and function. Additionally, sLNPs successfully delivered CRISPR-Cas9 mRNA and sgRNA for genome editing, as well as cytokine mRNA for immune modulation in the lungs. The sLNP platform demonstrated safety in adult mice, with no significant local or systemic tissue damage observed. These findings highlight the sLNP platform’s effectiveness and versatility in delivering diverse mRNA molecules, demonstrating its potential for applications ranging from gene editing to immunomodulation therapies. With further optimization, the sLNP system could pave the way for advanced mRNA-based treatments for lung diseases.</div></div><div><h3>Statement of Significance</h3><div>Almost all of the previously developed lipids for pulmonary mRNA delivery are amine-based. We designed and synthesized a group of lipids featuring the sulfonium charge-carrying group for mRNA delivery. This is the first demonstration of employing sulfonium lipid nanoparticles (sLNPs) for mRNA delivery to lung epithelial and immune cells <em>in vivo</em>. These sLNPs enabled efficient pulmonary delivery of diverse mRNA cargos, supporting applications such as bioluminescence imaging, gene editing, and immunomodulation. Club and ciliated cells as well as macrophages in the bronchoalveolar fluid, were successfully transfected. No sustained inflammation or toxicity was induced, highlighting the safety of these sulfonium lipid materials.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 616-633"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical and structural changes to the annulus fibrosus in response to Sub-failure cyclic loading","authors":"Jack Seifert ,&nbsp;Lance L. Frazer ,&nbsp;Dennis Maiman ,&nbsp;Alok Shah ,&nbsp;Sarah K. Shaffer ,&nbsp;Narayan Yoganandan ,&nbsp;James B. Sheehy ,&nbsp;Timothy Bentley ,&nbsp;Daniel P. Nicolella ,&nbsp;Brian D. Stemper","doi":"10.1016/j.actbio.2025.08.047","DOIUrl":"10.1016/j.actbio.2025.08.047","url":null,"abstract":"<div><div>This study aimed to quantify how repetitive tensile loading alters the mechanical and structural properties of the annulus fibrosus (AF). Mechanical changes were evaluated through a three-step protocol involving pre-damage characterization of dynamic and viscoelastic properties, damage induction using predetermined loading cycles (n=400, 1600, 6400, 12,800) to a specified strain magnitude (11 %, 20 %, 28 %, 44 %), and post-damage characterization of the same properties. Structural changes were assessed by subjecting tissue to damage cycles and staining with hematoxylin and eosin or fluorescing collagen hybridizing peptides (F-CHP). The results showed that damage cycles induced dose-dependent changes in the elastic and viscoelastic responses of the AF, decreasing the tissue’s response nearly 100 % of the pre-damage values. Quasi-static distraction to failure revealed that damage cycles influenced the transition strain magnitude, which ranged from 0.11 to 0.31, but did not alter the tissue’s ultimate properties. Structural analysis demonstrated cleft formation and collagen fiber uncrimping within the matrix, correlating with the magnitude of loading. However, F-CHP staining revealed no significant differences in denatured collagen fibers between damage groups. Overall, increasing damage parameters significantly decreased the dynamic and viscoelastic properties but did not affect the ultimate properties of the AF. Structural changes indicated disruption of elastic fibers within the AF microstructure without evidence of collagen fiber fractures. These findings provide new insights into the mechanics of healthy and damaged AF tissue, offering a foundational dataset for understanding AF degeneration and injury.</div></div><div><h3>Statement of Significance</h3><div>This study investigated the dose-dependent mechanical and structural changes in the annulus fibrosus under sub-failure cyclic loading, addressing a gap in the literature regarding how such loading alters annulus fibrosus properties. By systematically varying strain magnitudes and cycle counts, the work identifies dose-dependent changes in the AF’s elastic and viscoelastic behavior, along with structural alterations such as cleft formation and collagen fiber uncrimping. The integration of mechanical testing with histological analysis provides a comprehensive assessment of damage mechanisms in isolated AF tissue. These findings advance the current understanding of AF degradation and fatigue behavior, offering valuable insights for researchers studying spine biomechanics, injury prevention, and interventions aimed at mitigating spinal degeneration.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 478-490"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix and cytoskeletal tension gate stretch-induced calcium signaling","authors":"Patrick K. Jaeger ,&nbsp;Fabian S. Passini ,&nbsp;Barbara Niederoest ,&nbsp;Maja Bollhalder ,&nbsp;Sandro Fucentese ,&nbsp;Jess G. Snedeker","doi":"10.1016/j.actbio.2025.09.014","DOIUrl":"10.1016/j.actbio.2025.09.014","url":null,"abstract":"<div><div>The extracellular matrix (ECM) and mechanical loading shape cellular behavior, yet their interaction remains obscure. We developed a dynamic proto-tissue model using human tendon fibroblasts and live-cell calcium imaging to study how ECM and cell mechanics regulate mechanotransduction. Stretch-induced calcium signaling served as a functional readout. We discovered that ascorbic acid-dependent ECM deposition is essential for proto-tissue maturation and the recovery of stretch-induced calcium signaling at physiological strains. ECM synthesis and mechanical integration enhanced stretch sensitivity, reducing the strain needed to trigger a calcium response from ∼40 % in isolated cells to ∼5 % in matured proto-tissues. A strong correlation between tissue rupture and onset of calcium signaling indicates a mechanistic link to ECM damage. Disrupting ECM crosslinking, ECM integrity, cell alignment, or cytoskeletal tension reduced mechanosensitivity, demonstrating that stretch-induced calcium signaling depends critically on ECM–cytoskeleton integration and mechanics. Fundamentally, our work closely replicates stretch-induced calcium signaling observed in rodent tendon explants in an <em>in vitro</em> model and bridges the gap between cell-scale and tissue-scale mechanotransduction.</div></div><div><h3>Statement of significance</h3><div>The dysregulation of the tendon extracellular matrix is central to tendon disease, with controlled mechanical loading via physical therapy as the only established treatment. Tendon cells repair and maintain the matrix based on mechanical demands, yet how they sense loading and how matrix or cytoskeletal mechanics influence this process remains unclear. Animal models are often impractical, and existing <em>in vitro</em> models lack physiological relevance. We developed a dynamic <em>in vitro</em> model that replicates load-induced calcium signaling, a physiological tendon cell response observed in rodent tendons, and show that matrix and cytoskeletal mechanics are key to load sensation. Anchored to a validated sensory response, our model enhances physiological relevance and offers a platform to study tendon degeneration and recovery mechanisms.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 445-453"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biodegradable and anti-swelling peptide-based supermolecule hydrogel for eliminating ROS and inhibiting inflammation in acute spinal cord injury repair","authors":"Xiaolin Zhou ,&nbsp;Yanqiu Guo ,&nbsp;Zhan Gao ,&nbsp;Gan Lv ,&nbsp;Xiangyang Wang ,&nbsp;Mengpei Zhang ,&nbsp;Yunlong Zhou","doi":"10.1016/j.actbio.2025.08.043","DOIUrl":"10.1016/j.actbio.2025.08.043","url":null,"abstract":"<div><div>The treatment of spinal cord injury (SCI) presents a significant global medical challenge, as the difficulties associated with neuronal regeneration are compounded by elevated levels of reactive oxygen species (ROS) and an inflammatory microenvironment that ensues following SCI. Peptide-based supramolecular hydrogels exhibit robust advantages in repairing SCI due to their natural amino acid composition and biomimetic extracellular matrix characteristics following self-assembly. However, the potential for sequence designability remains underexplored, presenting an opportunity to develop highly bioactive peptide-based biomaterials. In this study, the tripeptide GHK, which is naturally present in human plasma, was incorporated into the peptide sequence (FFFGHK) to self-assembled to injectable, biodegradable and anti-swelling supramolecular hydrogel, and concurrently, endowed the supramolecular hydrogel with powerful antioxidant and anti-inflammatory functions. <em>In vitro</em> experiments demonstrated that FFFGHK supramolecular hydrogel was capable to eliminating ROS, inhibiting inflammatory response, saving cell apoptosis, accelerating the adhesion and proliferation of neurons, and promoting the differentiation of neural stem cells into neurons. It is noteworthy that the FFFGHK hydrogel exhibits a promising therapeutic effect in the treatment of SCI in rats. This has been shown to significantly enhance the recovery of autonomic motor functions and signal transduction, as well as promote neuronal regeneration at the SCI site in these animals. This work presents a single-component peptide self-assembled supermolecular hydrogel system, incorporating the bioactive peptide GHK in conjunction with phenylalanine. It offers critical insights into the design of peptide-based supermolecular hydrogels for bioactive applications.</div></div><div><h3>Statement of significance</h3><div><ul><li><span>•</span><span><div>Inflammation-related and ROS-related factors are significantly elevated in the peripheral blood of patients with spinal cord injury.</div></span></li><li><span>•</span><span><div>The natural antioxidant and anti-inflammatory tripeptide GHK self-assembles into an injectable, biodegradable, non-swelling supermolecular hydrogel.</div></span></li><li><span>•</span><span><div>The FFFGHK supermolecule hydrogel demonstrates the ability to eliminate ROS, inhibit inflammation, prevent cell apoptosis, enhance the adhesion and proliferation of neurons, and promote the differentiation of NSCs into neurons.</div></span></li><li><span>•</span><span><div>The FFFGHK supermolecule hydrogel has been shown to significantly enhance the recovery of autonomic movement and signal transduction in rats, as well as promote nerve regeneration.</div></span></li></ul></div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 193-204"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MXene-chitosan photo-responsive conduit for wireless optogenetic stimulation to enhance neural regeneration and functional recovery after optic nerve injury","authors":"Enoch Obeng ,&nbsp;Zhenyuan Xie ,&nbsp;Zhixing Li ,&nbsp;Wenyi Zhang ,&nbsp;Wei Wang ,&nbsp;Yuanli Wang ,&nbsp;Yan Zheng ,&nbsp;Zhaorong Wang ,&nbsp;Haojie Zhang ,&nbsp;Lanfang Sun ,&nbsp;Qingqing Yao ,&nbsp;Wencan Wu","doi":"10.1016/j.actbio.2025.08.045","DOIUrl":"10.1016/j.actbio.2025.08.045","url":null,"abstract":"<div><div>Optic nerve injury triggers progressive degeneration of retinal ganglion cells (RGCs) and axonal loss, driven by inhibitory microenvironmental factors such as glial scarring, myelin debris, and growth-inhibitory signaling. Physical stimuli such as photothermal and photoelectric stimulations have gained attention, yet little is known about their potential on normal cells or the optic nerve due to setbacks from over-exposure. Photothermal stimulus presents photoelectric cues and, at the same time, energy conversion for heat generation. Herein, a bio-functional platform was designed by incorporating W_1.33C <em>i</em>-MXene into a chitosan solution, further crosslinked with Genipin to give a porous, interconnected, and biodegradable conduit. The photoelectric platform allowed neural differentiation of PC12 cells through a substantial effect on the Calcium (Ca²⁺) ion channel. Further, we used the optic nerve crush (ONC) model to investigate the photo-stimulation effect of the conduit after ONC. Light stimulation of the WMC conduit promoted the protection of RGC and improved the visual function by modulating neural-related proteins and the downstream signaling cascade for nerve regeneration through the <span>l</span>-type voltage-gated calcium channel (L-VGCC). This multifunctional platform synergistically combines MXene's photoconductivity with chitosan’s biocompatibility, establishing a scalable strategy for wireless neural stimulation and tissue engineering–mediated functional recovery after central nervous system injury.</div></div><div><h3>Statement of significance</h3><div>The objective of this study was to design and fabricate a bio-functional, porous, and biodegradable platform by incorporating MXene into chitosan. This new conduit was expected to act as a photoelectric platform, allowing neural differentiation through a substantial effect on the calcium ion channel. W_1.33C <em>i</em>-MXene-chitosan (WMC) was the representative platform under a photothermal stimulus characterized by photoelectric cue and energy conversion to generate heat. In a rat optic nerve crush model, the conduit induced the protection of RGC and improved visual function by modulating neural-related proteins and the downstream signaling cascade for nerve regeneration through the <span>l</span>-type voltage-gated calcium channel (L-VGCC). This multifunctional platform synergistically combines MXenes' photoconductivity with chitosan’s biocompatibility, establishing a scalable strategy for wireless neural stimulation</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 205-221"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanotherapy: Modulating immune cell function in tissue regeneration and fibrosis","authors":"Niamh A. Ward ,&nbsp;Hannah Prendeville ,&nbsp;Eimear J. Wallace ,&nbsp;Parand Shokrani ,&nbsp;Lesley Trask ,&nbsp;Rachael Dillon ,&nbsp;Rachel Beatty ,&nbsp;Ellen T. Roche ,&nbsp;Garry P. Duffy ,&nbsp;Eimear B. Dolan","doi":"10.1016/j.actbio.2025.08.048","DOIUrl":"10.1016/j.actbio.2025.08.048","url":null,"abstract":"<div><div>Mechanotherapy – therapy which uses mechanical forces to produce a remedial or prophylactic effect – has great potential to improve therapeutic outcomes in the fields of regenerative medicine and drug delivery due to its adaptable and tunable nature. In particular, numerous <em>in vivo</em> studies have demonstrated the ability of mechanotherapies to improve functional muscle regeneration and modulate fibrosis. However, the cellular interactions that underlie these tissue level responses are poorly understood. To further harness the potential of mechanotherapies and inform their design and development, a more comprehensive understanding of immune cell responses to mechanical loading is required. Here, we review findings from preclinical investigations of mechanotherapies as both a treatment for muscular injury and as an immunomodulating component of medical implants. We then discuss the mechanosensitive nature of immune cells, emphasizing how mechanical loading and microenvironmental stresses can influence immune signalling pathways in the context of tissue regeneration and fibrosis. Finally, we offer our perspective on the future of the field, including the challenges facing mechanotherapeutic device development and the potential to further broaden the therapeutic targets of mechanotherapies.</div></div><div><h3>Statement of Significance</h3><div>Tissue regeneration following injury requires precise regulation of the innate and adaptive immune responses to restore tissue function and prevent fibrosis. Fibrotic tissue alters mechanical properties and impairs physiological function, making fibrosis a critical barrier to effective healing. Mechanotherapy, which uses mechanical forces for therapeutic effect, offers a promising approach to modulate immune responses and improve regenerative outcomes. Emerging evidence suggests that mechanical stimulation can attenuate fibrosis, yet the immune response to mechanical loading is highly dependent on loading parameters such as magnitude, frequency, and duration. Understanding how these parameters influence healing remains a key challenge. This review explores the relationship between mechanotherapy, immune modulation, and fibrosis, highlighting the potential for mechanotherapy to guide wound healing and improve clinical outcomes.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 34-53"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144982139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomimetic hydrogel platform reveals active force transduction from retinal pigment epithelium to photoreceptors","authors":"Sanna Korpela,&nbsp;Maija Kauppila,&nbsp;Viivi Karema-Jokinen,&nbsp;Lassi Sukki,&nbsp;Pasi Kallio,&nbsp;Heli Skottman,&nbsp;Soile Nymark ,&nbsp;Teemu O. Ihalainen","doi":"10.1016/j.actbio.2025.09.002","DOIUrl":"10.1016/j.actbio.2025.09.002","url":null,"abstract":"<div><div>In the eye, the retinal pigment epithelium (RPE) maintains the functionality and welfare of retinal photoreceptors and forms a tight, interlocked structure with photoreceptor outer segments (POSs). The RPE-retina interaction is difficult to recapitulate <em>in vitro</em>, limiting the studies addressing the retinal maintenance functions of the RPE. To overcome this challenge, we constructed a retina-mimicking structure using a soft polyacrylamide hydrogel coated with Matrigel. This structure was introduced to RPE cells’ apical side to model the RPE-retina interface <em>in vitro</em>. As a result, RPE cells attached to the hydrogels during culture, enabling further studies of cell adhesion and force transduction between the RPE-hydrogel with rheology and traction force microscopy. These methods were applied to a critical interactive process between the retina and the RPE: phagocytosis of the aged tips of POSs enabling their renewal. During phagocytosis, RPE cells imposed considerable traction forces to the POS particles. The force generation was actin-dependent, and the forces were significantly reduced by the disruption of RPE’s actin cytoskeleton. These results add another layer to the diverse interaction mechanisms between the RPE and the neural retina and pave the way for further studies of the RPE-retina interplay.</div></div><div><h3>Statement of significance</h3><div>In the eye, light sensing neural retina interacts and functions jointly with the underlying epithelial tissue (retinal pigment epithelium, RPE). Impairments in this physical interaction can cause retinal degeneration and blindness. However, currently we are missing cell culture model systems of the RPE and the retina, where this interaction could be manipulated and studied. To address this, we developed a hydrogel-based retina-mimicking structure cultured with RPE cells. This platform enabled studies of the interface, particularly the essential renewal process between the RPE and retinal photoreceptor cells. For the first time, we provided direct evidence that this process involves significant force transmission between the RPE and the retina. These findings uncover a previously unrecognized mechanobiological interaction between neural and epithelial cells in the eye.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 537-549"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of oxidized hyaluronic acid based hydrogels for neuronal tissue engineering: Effects of matrix stiffness on primary neurons","authors":"Markus Lorke ,&nbsp;Sonja Kuth ,&nbsp;Renato Frischknecht ,&nbsp;Aldo R. Boccaccini","doi":"10.1016/j.actbio.2025.09.007","DOIUrl":"10.1016/j.actbio.2025.09.007","url":null,"abstract":"<div><div>Due to the presence of hyaluronic acid (HA) in the human body, specifically the brain, HA-based hydrogels are promising candidates for neural tissue engineering applications. Providing the right mechanical and biological properties is essential to mimic the native tissue with the aim of achieving stimulatory effects and promoting regeneration. In this study, HA was oxidized using sodium metaperiodate (NaIO4) to produce oxidized hyaluronic acid (OHA). Hydrogels were then synthesized by crosslinking OHA with gelatin (GEL) through a Schiff base reaction, facilitated by microbial transglutaminase (mTG). The hydrogels were further modified to achieve different mechanical properties, and their long-term stability was investigated by varying the concentrations of OHA, GEL, and mTG. Compression tests as well as swelling/degradation studies confirmed an important influence of the precursor amount on the mechanical characteristics in these hydrogels. Increasing the amount of GEL and OHA at the same time led to a higher effective modulus and beneficial properties regarding long-term stability, and vice versa. Microstructural analyses proved the connection of the respective mechanical properties to the crosslinking density and mesh size. To investigate the applicability of the different hydrogel concentrations as ECM substitutes, three hydrogel compositions were selected and evaluated using E18 primary neurons. The experiments showed that the neuron survival rate as well as their development was optimal at lower ratios of the components with higher crosslinking amount and an intermediate stiffness (modulus) of ∼0.5 kPa. The results thus confirmed the versatility of the OHA-GEL system to be used as matrix in brain tissue engineering.</div></div><div><h3>Statement of significance</h3><div>Neural damage poses a significant medical challenge, with the mechanics of native neural tissue still not fully understood. Hyaluronic acid (HA), a natural component of the brain's extracellular matrix, holds promise for neural tissue engineering. This study developed a hydrogel by oxidizing HA (OHA) and crosslinking it with gelatin (GEL) using a Schiff base reaction and microbial transglutaminase (mTG). By adjusting OHA, GEL, and mTG concentrations, the hydrogels were engineered to mimic brain tissue stiffness and maintain long-term stability. Compression and microstructural analyses linked crosslinking density and mesh size to mechanical properties. Testing with primary neurons demonstrated optimal survival and growth at intermediate stiffness, emphasizing the OHA-GEL system’s potential for advancing neural repair.</div></div>","PeriodicalId":237,"journal":{"name":"Acta Biomaterialia","volume":"205 ","pages":"Pages 454-466"},"PeriodicalIF":9.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}